Dataset Information

Sex-specific molecular hallmarks of atherogenesis susceptibility in senescence-accelerated mice

ABSTRACT: The senescence-accelerated mouse (SAM) model has been extensively used to study neurological alterations associated with aging. Although the SAM model is also useful to study vascular aging, there is still work to be done to better define its utility as a model of atherosclerosis, since contradictory data have been published and sex seems to play a crucial role in potential divergences. With this in mind, we aimed to decipher the molecular mechanisms underlying the potentially higher atherogenesis risk of SAMP8 mice, analyzing the aorta of 10 months-old animals by means of in-depth proteomic analysis, considering sex- specific differences. Validation of the results obtained were performed by western blot in an independent cohort of mice, as well as in human aortic smooth muscle cells (HASMC). Besides, an exhaustive lipoprotein and glycoprotein analysis was performed in plasma. Distinct proteomic, lipoprotein and glycoprotein profiles have been found in SAMP8 mice, according to sex. Male SAMP8 mice evidenced increased atherogenesis susceptibility due to several sex- specific alterations: 1) increased number of VLDLs, as well as in their cholesterol and TG content; 2) upregulation of inflammatory glycoproteins in plasma; and 3) increased features of SASP and vascular calcification: upregulation of exocytic vesicular transport and downregulation of the protein Gas6. On the contrary, female mice showed a much better proteomic and lipoprotein profile and only the decrease of the atheroprotective protein NRP1 as a sex-specific pathological feature. The results obtained suggest that male SAMP8 mice can develop atherosclerosis under a HFD while female SAMP8 mice may be less susceptible to atherogenesis.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Aorta

DISEASE(S): Atherosclerosis

SUBMITTER: Fernando de la Cuesta Marina

LAB HEAD: Fernando de la Cuesta Marina

PROVIDER: PXD057104 | Pride | 2025-09-02

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	rawdata_proteomexchange.7z	Other
	spectronaut_searchresults_proteomexchange.7z	Other

Items per page:

1 - 2 of 2

Publications

Sex-specific molecular hallmarks point to increased atherogenesis susceptibility in male senescence-accelerated mice.

González-Moro Ainara A Herranz Estela E Rodríguez de Lope Miriam Morales MM Sanchez-Pajares Ibone Rubio IR Sánchez-Ramírez Jorge J Rivera-Tenorio Alan A Shamoon Licia L Sánchez-Ferrer Carlos Félix CF Peiró Concepción C de la Cuesta Fernando F

Life sciences 20250304

<h4>Aims</h4>The senescence-accelerated mouse (SAM) model has been extensively used to study neurological alterations associated with aging. The SAM model has also proved to be useful in the study of vascular aging, but there is still work to be done to better define its utility as a model of atherosclerosis, since contradictory data have been published and sex seems to play a crucial role in potential divergences.<h4>Materials and methods</h4>With this in mind, we aimed to decipher the molecula ...[more]

PMID: 40049367

Similar Datasets

Project description:Aims: We investigate sex differences and the role of oestrogen receptor beta (ERbeta) in a mouse model of pressure overload-induced myocardial hypertrophy. Methods and results: We performed transverse aortic constriction (TAC) or sham surgery in male and female wild-type (WT) and ER knockout (ERbeta-/-) C57Bl6 mice. All mice were characterised by echocardiography and haemodynamic measurements and were sacrificed nine weeks after surgery. Left ventricular (LV) samples were analysed by microarray profiling, real-time RT-PCR and histology. After nine weeks, WT males showed more hypertrophy and heart failure signs than WT females. Notably, WT females developed a concentric form of hypertrophy, while males developed eccentric hypertrophy. These sex differences were abolished in ERbeta-/- mice. ERbeta deletion augmented the TAC-induced increase in cardiomyocyte diameter in both sexes. Gene expression profiling revealed that male WT hearts had a stronger induction of matrix-related genes and a stronger repression of mitochondrial genes than female hearts. ERbeta-/- mice exhibited a different transcriptome. Induction of pro-apoptotic genes after TAC occurred in ERbeta-/- mice of both sexes with a stronger expression in ERbeta-/- males. Histological analysis revealed, that cardiac fibrosis was more pronounced in male WT TAC than in female mice. This was abolished in ERbeta-/- mice. Apoptosis was significantly induced in both sexes of ERbeta-/- TAC mice, but it was most prominent in males. Conclusion: Female sex offers protection against ventricular chamber dilation in the TAC model. Both the female sex and ER attenuate the development of fibrosis and apoptosis; thus slowing the progression to heart failure. The influence of sex (male/female) and estrogen receptor beta expression (ERbeta knockout/wildtype) on cardiac hypertrophy (transverse aortic constriction/sham operated) was investigated. The left ventricular transcriptome of four individual mice for each combination of the three factors (sex, genotype, surgery) was detected with Affymetrix RAE 430 2.0 GeneChip arrays.

Project description:Background & Aims: Cholangiocarcinomas (CCAs), heterogeneous biliary tumors with dismal prognosis, lack accurate early-diagnostic methods, especially important for individuals at high-risk (i.e., primary sclerosing cholangitis (PSC)). Here, we searched for protein biomarkers in serum extracellular vesicles (EVs). Methods: EVs from patients with isolated PSC (n=45), concomitant PSC-CCA (n=42), PSC who developed CCA during follow-up (PSC to CCA; n=25), CCAs from non-PSC etiology (n=56), hepatocellular carcinoma (n=34) and healthy individuals (n=55) were characterized by mass-spectrometry. Diagnostic biomarkers of PSC-CCA, non-PSC CCA or CCAs regardless etiology (pan-CCAs) were defined, and their expression was evaluated in human organs/tissues and within CCA tumors at single-cell level. Prognostic EV-biomarkers for CCA were investigated. Results: High-throughput proteomics identified candidate diagnostic biomarkers for PSC-CCA, non-PSC CCA or pan-CCA, as well as and for differential diagnosis of intrahepatic CCA and HCC, that were cross-validated by ELISA using total serum. Machine learning logit modelling disclosed CRP/FRIL/Fibrinogen algorithm with diagnostic value for early-stage PSC-CCA vs isolated PSC (AUC=0.944; OR=82.0), overpowering CA19-9 (AUC=0.735; OR=9.3). An algorithm combining CRP/VWF/PIGR/ /Fibrinogen allowed the diagnosis of early-stage non-PSC CCAs compared to healthy individuals (AUC=0.999; OR=1115). Noteworthy, levels of Fibrinogen/CRP/PIGR/FRIL showed predictive capacity for CCA development in patients with PSC before clinical evidences of malignancy. Multi-organ transcriptomic analysis revealed that serum EV-biomarkers were mostly expressed in hepatobiliary tissues, and scRNA-seq and immunofluorescence analysis of CCA tumors showed their presence mainly in malignant cholangiocytes. Multivariable analysis unveiled EVprognostic biomarkers independent to clinical features, with COMP/GNAI2/CFAI and ACTN1/MYCT1/PF4V associated negatively or positively to patients’ survival, respectively. Conclusions: Serum EVs contain protein biomarkers for the prediction, early diagnosis and prognosis estimation of CCA, representing a novel tumor cell-derived liquid biopsy for personalized medicine.